S1827 MCP-1 Inhibits DNA Synthesis in Rat Pancreatic Stellate Cells

Abstract

Activated pancreatic stellate cells (PSCs) synthesize various kinds of cytokines and chemokines including monocyte chemoattractant protein-1 (MCP-1) and play major roles in promoting inflammation and fibrogenesis in the pancreas. MCP-1 is a potent chemotactic factor for leukocytes and it has recently been shown that the target is not restricted. The aim of this study was to investigate whether MCP-1 exerts a biological effect on PSCs. Cultured rat PSCs secreted MCP1 independent of the concentration of transforming growth factor-β 1 (TGF-β 1) in the culture media. Although PSCs lack the typical receptor system (C-C chemokine receptor 2 (CCR2)), MCP-1 inhibited DNA synthesis in PSCs without activation, suggesting the presence of CCR2-independent MCP-1 signaling pathway. Further, MCP-1 inhibited the proliferation of PSCs in which TGF-β 1/Smad pathway was blocked by the dominant-negative Smad2/3 over-expression. MCP-1 did not affect the phosphorylation state of mitogen-activated protein kinase (MAPK), Akt, nor epidermal growth factor receptor (EGFR). Taken together, MCP-1 inhibited DNA synthesis of cultured rat PSCs in an autocrine or paracrine manner without activation and this effect was exerted through CCR2-independent and TGF-β 1/Smad-independent pathway. These data provide new insights to better understand MCP-1 participation in pancreatic inflammation and also to develop a new strategy for its treatment.